Page 75 - Haematologica Vol. 109 - July 2024

ARTICLE - Familial germline pathogenic alleles and hematologic malignancies Q. Feng et al.
Discussion
This is the first study to our knowledge using purely popula- tion-based, no patient contact resources to examine genetic causes of family-based cancer clustering. We demonstrate that deleterious variants shared between family members contribute to early-onset hematologic cancers and that these can be revealed using California’s linked birth and cancer registries and neonatal blood spot Biobank. This establishes the utility of these population-based resources to study familial cancer predisposition successfully, as well as to identify germline inherited risk alleles among varied ancestral groups. The profile of germline P/LP variants across ancestral/ethnic groups share similarities as well as distinc- tive characteristics. Consistent with previous findings, we note that individuals with familial early-onset hematologic cancers harbor deleterious germline variants in TP53, GATA2, and ATM.9,21 Pathogenic variants in TP53 have been associated with many hematologic cancers including lymphoblastic,22 myeloid leukemias,23 and lymphomas.24-26 Deleterious ger- mline variants in GATA2 have been associated with myeloid malignancies,27,28 and variants in ATM have been associated with T-cell prolymphocytic leukemia,29 mantle cell lympho- ma,30 and gliomas.31 The non-shared SMARCA4 germline P/ LP variant that we identified in a subject with teratoma is consistent with previous reports that have described ger- mline mutations in SMARCA4 for teratomas.32,33
Some P/LP variants exhibit novelty. The shared SBF2 in one NLAIAN family is a novel discovery in childhood cancers. SBF2 is associated with cancer by a newly identified long non-cod- ing RNA, SBF2-AS1. SBF2-AS1 was initially characterized in non-small cell lung cancer,34 and has recently been reported to be over-expressed in multiple adulthood cancers in an East Asian population.35-46 P/LP variants in NOD2 is also a novel discovery in childhood cancers, and, intriguingly, one variant was found in 2 siblings who both developed HL. NOD2 is a gene that is involved in immune response,47 and has been associated with colorectal cancer.48 In addition, we also re- ported a shared FLG mutation in association with childhood hematologic cancers. Somatic mutations of this gene have been reported to be associated with autoimmune diseases.49 A HABP2 mutation was shown to be shared between siblings with malignant large-B-cell lymphoma and neuroblastoma. HABP2 encodes a serine protease, and an inactivating mu- tational variant (G534E) distinct from the one found here was previously linked to extramedullary thyroid neoplasia.50 The nonsense mutation found here in this gene (C290*) has not been reported previously and likely represents a private familial mutation.
There are several strengths and limitations of this study. A major strength is the linkage of population-based cancer registries to identify subjects for sequencing. Thus, we have established a novel perspective on genetic predisposition that drives the excessive familial risk of early-onset hematologic cancers without selection or recruitment bias that may af-
fect clinic or referral-based studies. We found P/LP alleles in about a quarter (25%) of families, as well as many suspect VUS alleles in addition, and an additional 7 families (22%) that have a P/LP mutation in one child only. This compares with the approximately 5-10% frequency of such alleles in sample series chosen without regards to family history.3-6 A study that examined predisposition in the context of multiple sibling myeloid cancers in families using anecdotal clinical referral recruitment of families and liberal mutation identi- fication criteria found candidate mutations in 83 of 86 fami- lies.51 While we also similarly found VUS and P/LP mutations in nearly every subject, we emphasize the reporting of highly curated L/LP alleles, which in our 64 subjects yielded 23 (36%) mutations. Given the large size of our base population and definition of “cancer families” as those with a minimum of only 2 cases, it is likely that some families will be afflicted by multiple cancers by chance without predisposing alleles or be influenced via familial sharing of an environmental exposure. Still, our 36% yield compares with a 4.4% yield in an assessment of leukemia-associated P/LP mutations in a large study of sporadic patients,4 attesting to the power of population-based recruitment in the current investigation. Benefiting from the highly diverse population in California, we are the first research group that has assessed the vari- ation in genetic predisposition in association with familial hematologic cancer risk in multiple ancestral/ethnic groups over a defined population, appraising cancer predisposi- tion in a selection-bias free, consent-bias free population. However, limited by the length of time in data collection and the rarity of childhood cancers, we have only identified a selection of mutations that are unique to an ancestral/ ethnic group. In addition, we have no way to evaluate or confirm the impact of non-shared P/LP alleles inherited by chance by those siblings that did not share a P/LP allele. Also, limited to analysis of SNV and indels, we did not assess variation in copy number or epigenetic alterations that may be potentially pathogenic.
Cancer risk is increased by both genetic and environmental factors. Family members are generally exposed to the same environments and therefore those in-common environments may contribute to the observed familial cancer clustering. To understand such clustering better, concomitant assessments of environmental factors in coordination with germline genet- ics should be considered for future studies. Such analyses will help to establish the role of strong cancer predisposition variants more definitively among different ancestral/ethnic groups, and whether such mutations harbor varied pene- trance in the context of different ancestral backgrounds and environments. This type of evaluation is increasingly critical in the intermixed population of California and other world regions, and has profound implications for family genetic counseling in the context of improved cancer patient survival.
Disclosures
No conflicts of interest to disclose.
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